The hematopoietic stem and progenitor cell (HSPC) represents a diverse population of cells responsible for maintaining and regenerating the hematopoietic system. Maintaining the proper function of these cells, and particularly the long-lived self-renewing hematopoietic stem cell, is essential for health and survival. In HIV disease there are serious deficits involving hematopoietic function that cannot simply be explained by HIV-1 infection of T-cells and macrophages. It has been hypothesized that HIV-1 can directly infect HSPC leading to hematopoietic dysfunction. This hypothesis is supported by studies showing that HSPC express the receptors necessary for HIV-1 infection and recent studies demonstrating direct infection of HSPC by HIV. It has also been demonstrated that HIV can establish a latent infection in HSPC, suggesting that HSPC could serve as an important reservoir for HIV-1 in drug treated individuals. However, the conclusions of these studies are disputed since they are based principally upon in vitro or ex vivo HIV-1 infection of HSPC. We propose to address the hypothesis that HSPC can be infected and function abrogated by using a model system, the BLT mouse model, which more closely mimics natural HIV-1 infection in the bone marrow (BM). Investigation of HIV-1 infection of HSPC further requires the recognition that HSPC are not a uniform population. It has been known for decades that the majority of HSPC purified experimentally from bone marrow represent precursor cells that are destined to differentiate to specific lineages. Only a small fraction of these cells represent true hematopoietic stem cells which have the ability to self-renew indefinitely as well as give rise to the committed progenitor cells. In addition, our recent studies of HSPC in non-human primates demonstrate that even long-lived stem cells have different behaviors in regards to their contribution to hematopoietic output and their relative distribution to lymphoid versus myeloid progeny. Thus, it is critical that studies of HIV-1 infection of HSPC should investigate the consequences of infection upon individual HSPC rather than the entire population. This can be accomplished by a method known as clonal tracking, whereby individual HSPC are genetically marked by integrating lentiviral vectors and then tracked after transplant and repopulation. By combining clonal tracking with FACS separation of hematopoietic cell sub-populations, we can investigate the consequences of HIV infection on the behavior of HSPC clones and their progeny. We have used this methodology effectively to study the behavior of HSPC clones in non-human primates and propose to extend this methodology to the impact of HIV-1 infection upon HSPC.